| Abstract | Background: Therapeutic drug monitoring (TDM) of vancomycin has been
proven to maximize therapeutic outcomes and minimize toxicity when
conducted appropriately. The quality of vancomycin TDM services in many
settings remains to be explored. Vancomycin still poses many questions
regarding its clinical pharmacokinetic parameters, optimal dosing, and TDM
strategies in unstudied populations.
Objectives: This project comprised three distinct sequential phases. Phase I
aimed to evaluate the appropriateness of routine vancomycin TDM service in
Qatar and its impact on clinical outcomes. Phase II aimed to evaluate the
relationship between vancomycin 24-hr-AUC/MIC ratios and cure; and to
compare the clinical outcomes between peak-trough-based and trough-onlybased
vancomycin TDM approaches. Phase III aimed to determine
vancomycin population pharmacokinetics considering patient-specific
covariates and to assess the need for vancomycin dosing nomograms that are
specific to Qatar’s population.
Methods: Phase I was a retrospective chart review that was conducted on
adult non-dialysis vancomycin TDM cases electronically documented
between January 2014 and August 2016 in Al-Wakrah Hospital (AWH), Al-
Khor Hospital (AKH), and Hamad General Hospital (HGH). Evidence-based
criteria were applied to evaluate TDM appropriateness. Descriptive and inferential statistical analyses were applied using SPSS v.23.
Phase II was a multicenter pragmatic parallel prospective randomized
controlled trial (RCT) that was conducted from February 2016 to September
2016 in HGH, AWH and AKH. Adult non-dialysis patients who were initiated on
vancomycin treatment were randomized to intervention arm (peak-trough-based
vancomycin TDM) or control arm (trough-only-based vancomycin TDM). Multiple
steady-state vancomycin blood samples were obtained for AUC determination.
24-hr-AUC calculation was conducted using NONMEM version 7.3
(ICON,USA) and PDx-Pop version 5.2 (ICON,USA), utilizing the population
pharmacokinetic model developed in Phase III. Descriptive, inferential, and
CART statistical analyses were applied using SPSS v.23.
Phase III was a population pharmacokinetic analysis that was conducted
based on the principles of non-linear-mixed-effects-modeling. Internal
validation of the final model was applied by bootstrap analysis of 500 data
replicates. The agreement between the final parameter estimates,
95%confidence intervals of the developed final model and the bootstrap
results were compared. To evaluate the need for population-specific dosing
nomograms, the generated population parameter estimates were compared
against literature reported values in similar populations. Phase III procedures
were conducted using NONMEM v.7.3, (ICON,USA) and PDx-Pop v.5.2
(ICON,USA).
Results: Phase I: Two hundred eight vancomycin TDM cases involving 99
patients were evaluated. Most of the evaluated TDM cases (90.4%, n=188)
were inappropriately conducted. The indications for TDM requests were
appropriate in most of the cases (77.4%, n=161). Most of the blood samples
were collected at incorrect times (70.7%, n=147), and incorrectly labelled (81.7%, n=170). Overall, the actual sampling times revealed that most
vancomycin blood samples (61.5%, n=128) corresponded to vancomycin random
concentrations. Furthermore, high rates of inappropriate post- analytical actions
were recorded (65.9%, n=137). Inappropriate compared to appropriate vancomycin
TDM practices were associated with significantly lower therapeutic cures [47.3%
vs .75%; p-value=0.009] and longer hospitalizations [median[IQR]: 26[31] vs.
13[47.7] days; p-value=0.103]. All patients who experienced neutropenia (100%,
n=6) received inappropriate vancomycin TDM service. Similarly, of all patients who
experienced nephrotoxicity, 84.6% (n=11) received inappropriate vancomycin
TDM service.
Phase II: Sixty-five patients were enrolled in the RCT [trough-only-group:35
patients vs. peak-trough-group:30 patients]. Peak-trough-based vancomycin
TDM was significantly associated with higher therapeutic cure rates
compared to control group [76.7% vs .48.6%; p-value=0.02]. Compared to
the control group, peak-trough-based vancomycin TDM recipients required
less average vancomycin single doses and total daily doses by 370mg/dose
and 927mg/day, respectively [p-value<0.05]. Similarly, trough-only-based
vancomycin TDM recipients required higher cumulative vancomycin doses
versus the intervention group [median[IQR]: 19500[25860] mg vs.
13250[14925] mg; p-value>0.05]. CART identified creatinine
clearance(CrCl), 24-hr-AUC and TDM approach as significant determinants
of therapeutic outcomes. All patients with CrCl≤7.85L/hr who achieved 24- hr-
AUC≤1255.98mg.hr/L and received peak-trough-based vancomycin TDM achieved
clinical success [100%, n=19]. In contrast, patients with CrCl≤7.85L/hr who
maintained 24-hr-AUC≤1255.98mg.hr/L but received trough-only-based vancomycin
TDM experienced 29.4% (n=5) failure rates. Maintenance of 24-hr-AUC>564.117mg.hr/L was identified as the
breakpoint of cure in trough-only-based TDM recipients [84.6%, n=11].
Phase III: A total of 769 vancomycin blood concentrations obtained from 156
subjects were analyzed. A two-compartment model with a proportional
residual error and between-subject variability modeled on clearance (Cl),
central compartment volume of distribution (Vc) and intercompartmental
clearance (Q) best described vancomycin disposition. The physiologic
parameters Cl and Vc, were estimated with good precision [Cl:5.23L/h,
95%CI: 4.72-5.74; Vc:44L, 95%CI: 37.7-50.3]. CrCl and age were
significant covariates in the final model (p-value<0.01). Interindividual
variability for Cl, Vc and Q was 38.9%, 42.7%, and 97% in the final model,
respectively. Fixed effects parameters were estimated with reasonable
precision and lied within 95%CI of bootstrap analysis. The population
parameter estimates were similar to literature reported 2-compartment model
estimates in adult non-dialysis patients.
Conclusion: This work suggests that the improvement of the quality of
vancomycin TDM practices, maintenance of a 24-hr-AUC between 564.117-
1255.98 mg.hr/L, and the implementation of peak-trough-based vancomycin
TDM, are three main strategies that will potentially improve health-care
outcomes associated with vancomycin treatment. The findings have
important implications on developing strategies that will improve rational
TDM practices in Qatar, the Middle East region and possibly worldwide |
